Pharmaceutical R _ D Summit-2011 - OMICS Group

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					Joint Meeting
2nd World Congress on
Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011
International Conference on
Pharmaceutics & Novel Drug Delivery Systems
                                                                                                              doi: 10.4172/0975-0851.1000105
Joint Meeting
                                         2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                         International Conference on Pharmaceutics & Novel Drug Delivery Systems

Evaluation of
bioequivalence of generic                         R    egulatory changes established in Mexico in 1998 made mandatory evaluation
                                                       of interchangeability of generic drugs, by comparison of dissolution profile or
                                                  demonstration of bioequivalence. Since then, a lot of studies of bioequivalence have
drugs: The Mexican                                been conducted in Mexico. Several important aspects have been observed during the
experience                                        conduction of such studies. On one hand, it has been observed that most of the cases
Francisco J. Flores-Murrieta
                                                  in which bioequivalence was not concluded was in drugs that are classified as type IV
                                                  according their solubility and permeability, whereas, bioequivalence was concluded in
Instituto Politecnico Nacional and Unidad de
Investigacion en Farmacologia, Mexico
                                                  drugs classified as type I and III (high solubility) although differences in dissolution
                                                  profile was observed and, moreover, in different pharmaceutical formulations, i.e.
                                                  capsule against tablet. On the other hand, when pharmacokinetic parameters obtained
                                                  in these studies were compared with the values reported in other populations, it has
                                                  been observed that increased levels are reached in Mexicans in comparison with those
                                                  reported in Caucasians for drugs metabolized by CYP3A4 and for drugs that are
                                                  substrates of p-glycoprotein. Such differences were reflected in a higher incidence of
                                                  side effects and suggest interethnic differences in the pharmacokinetics of this kind of
                                                  drugs. According to these results, it is mandatory to re-evaluate dosage regimes used
                                                  in Mexico according to our population characteristics.

                                                      Francisco Javier Flores-Murrieta has completed his Ph.D in 1991 from Centro de Investigación
                                                   y de Estudios Avanzados del Instituto Politécnico Nacional. Currently, he is the head of the Unit
                                                   of Pharmacology Research of the Instituto Nacional de Enfermedades Respiratorias Ismael
                                                   Cosio Villegas and Professor of Escuela Superior de Medicina del Instituto Politécnico Nacional.
                                                   He has published more than 100 papers in reputed journals on Pharmacokinetics (preclinical
                                                   and clinical), analytical methods and analgesia, 5 book chapters and 1 book. He has supervised
                                                   more than 30 posgrade thesis. He has received several awards in Mexico, including “Honors
                                                   of the National Youth Award” and the “Mexican Academy of Sciences Award”. He served as
                                                   president of the Western Pharmacology Society and the Mexican Pharmacology Association
                                                   and currently he is Fellow of the American College of Clinical Pharmacology and member of
                                                   the editorial board of Pharmacology and Pharmacy, The Open Clinical Trials Journal and The
                                                   Proceedings of the Western Pharmacology Society.
                                                                                                                doi: 10.4172/0975-0851.1000105
Joint Meeting
                                           2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                           International Conference on Pharmaceutics & Novel Drug Delivery Systems

Bioavailability and
Bioequivalence in                                   B   ioequivalence (BE) studies are scientific methods that allow comparison of
                                                        different medicinal products containing the same active substance, or different
                                                    batches of the same medicinal products or, in a broad sense, different routes of
veterinary drugs- The                               administration of the same product. In Veterinary Medicine, this issue can involve a
European issue                                      dual aspect: i) the effectiveness of the drug in patients (animal) and ii) the consumers’
                                                    health (human). High efficiency in the field of Veterinary Medicine, particularly in
                                                    animal production (globally requested for the food supply), is achieved nowadays by
Veterinary School, University of Pisa, Italy
                                                    the employment of veterinary medicines and feed additives. Because of the lower cost
                                                    of development and competition in the market place, generic drugs usually sell for less
                                                    than the brand name drug products from the original manufacturers (innovators or
                                                    pioneers). This fact has led many to believe that generic drugs are somehow inferior
                                                    to brand-name products. The use of animal health products in animal production
                                                    however, should be done following the standards on Good Clinical Practice (GCP) on
                                                    Veterinary Drugs Use. Thus, only products approved for food producing animals use
                                                    and their generic formulation (that have statistically proven BE) should be employed.
                                                    Several problems concerning peculiar routes of administrations, variability among
                                                    the subjects, etc…, have been recovered in veterinary drugs rather than the human
                                                    drugs, for the assessment of the BE. The new EU guidelines report narrow rules on BE
                                                    determination, but lack of rigid rules on excipients. Anyhow, EMEA mandates that
                                                    the generic veterinary drugs must be as safe and effective as the brand-name drugs.

                                                         Mario Giorgi has completed his PhD and pharmacology specialization studies at the age
                                                      of 27 years in Pisa University School of Pharmacy/Medicine. He is aggregate professor in
                                                      P&T and in charge for the direction of the Veterinary Pharmacology & Toxicology Research
                                                      Division of the University of Pisa. He has published 50+ papers in reputed journals and assists
                                                      several journals in reviewing processes. He is a member of several Pharmacology & Toxicology
                                                      international societies as well as Italian Olympic Committee. He has several international
                                                      scientific partnerships (China, Israel, Poland, Iran, South Korea, and Kazakhstan).
                                                                                                             doi: 10.4172/0975-0851.1000105
Joint Meeting
                                       2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                       International Conference on Pharmaceutics & Novel Drug Delivery Systems

Design and
characterization of novel                       T    o achieve successful ovarian cancer gene therapy, safe and efficient gene delivery
                                                     systems are needed. Non-viral delivery vectors have several potential advantages
                                                (low toxicity, lack of immune response, ease of production) over the widely used viral
phytanyl substituted                            vectors for delivering therapeutic genes. Gemini surfactants are a family of surfactants
gemini surfactants                              containing two surfactant monomers that are linked by a spacer group. An advantage
for Improved DNA                                of this structure is increases in gemini surfactant-DNA binding efficiencies. Based on
                                                a rational design approach, a series of novel phytanyl substituted gemini surfactants
transfection vectors                            were synthesized and characterized. The nanoparticles were composed of the gemini
Haitang Wang1 and Shawn Wettig2                 surfactant, plasmid coding for GFP, and one neutral lipid, DOPE. The transfection
Chemistry, University of Waterloo, Canada
1                                               particles at varying charge ratios of gemini surfactant to DNA were characterized using
School of Pharmacy, University of Waterloo,
                                                measuring size and zeta potential. In vitro study of the phytanyl gemini surfactants
                                                as gene delivery vectors in ovarian cancer cells was investigated. The transfection
                                                particles at different charge ratios demonstrated varying, but significant transfection
                                                efficiencies. At a charge ratio of 5:1, the phy-3-12 and phy-3-18 showed the highest
                                                transfection efficiency, while the phy-3-16 had the highest transfection efficiency
                                                at the charge ratio of 2:1. Furthermore, the transfection particles were determined
                                                by small angle X-ray scattering (SAXS). The structure obtained by SAXS indicated
                                                that the activity of gemini surfactants as gene delivery vectors can be related to the
                                                structure of the particles.

                                                    Haitang Wang is currently completing a PhD in the Department of Chemistry at the University
                                                 of Waterloo under the supervision of Dr. Shawn Wettig. Previously Haitang has completed a
                                                 BSc in Chemistry and MSc in Biological Science and Technology at the Dalian University of
                                                 Technology in China, and a MSc in Biology at the University of Waterloo. Her research interests
                                                 are in safe and efficient gene delivery systems, non-viral delivery vectors, the use of derivatives
                                                 of gemini surfactants to improve DNA transfection, and the mechanism of how the structure of
                                                 gemini surfactants affects cancer gene therapy.
                                                                                                   doi: 10.4172/0975-0851.1000105
Joint Meeting
                                   2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                   International Conference on Pharmaceutics & Novel Drug Delivery Systems

On Bioequivalence
Metrics                                     I  n a typical bioequivalence trial, the determination of the area under the
                                               concentration-time profile, AUC, and the maximum concentration, Cmax, are the
                                            most commonly used measures to assess the bioequivalence of two drug formulations.
Husam Awni Bayoud                           The United States Food and Drug Administration (FDA) (1992) stated that two
Fahad Bin Sultan University, KSA            formulations, test and reference, are bioequivalent if 90% confidence interval of the
                                            ratios Test AUC/Reference AUC and Test Cmax/Reference Cmax lie between 0.8 and
                                            1.25 (or between -0.22 and 0.22 after the log-transformation).
                                                Several authors have noticed that the equality of AUC and Cmax is necessary but
                                            not sufficient condition for the bioequivalence of two drug formulations (see e.g.;
                                            Rescigno and Powers, 1997). This is because these pharmacokinetic parameters do not
                                            take the profile shape in consideration. In view of this, several authors in the literature
                                            have proposed various bioequivalence metrics to assess the bioequivalence of two
                                            formulations by estimating the similarity (or dissimilarity) of two profiles taking the
                                            important differences between profiles into account.
                                                 A new bioequivalence metric has been proposed to assess the bioequivalence of
                                            test and reference formulations by estimating the percentage of common area under
                                            their profiles. The performance, in terms of the statistical power, of the previously
                                            proposed and the new bioequivalence metrics was evaluated by simulating cross-over
                                            bioequivalence trials.
                                                                                                        doi: 10.4172/0975-0851.1000105
Joint Meeting
                                 2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                 International Conference on Pharmaceutics & Novel Drug Delivery Systems

Bioequivalence, Rate of                   T     o determine the relative bioavailability and bioequivalence in fasted and semi-
                                                fed states, and compare the rate and extent of absorption and food effect of two
                                          formulations of paracetamol + caffeine products: Panadol Extra (currently-marketed
Absorption, and Food                      product) and Panadol Extra Advance. This study was designed as a single-center,
Effect Study of a New                     open-label, randomized, single-dose, 4-way (2 formulations and 2 food states)
Paracetamol/Caffeine                      crossover study. In each period, two caplets of either Extra Advance or current Extra,
                                          each totaling 1000 mg paracetamol + 130 mg caffeine, were orally administered.
Formulation in Healthy                    Thirty subjects were enrolled with all completing the study. Serial blood samples
Volunteers                                were collected at pre-dose until 10-hours post-dose. Plasma samples were assayed for
Dongzhou J. Liu1, Mitchell Kotler1 and    paracetamol and caffeine concentration using HPLC/MS methods. Pharmacokinetic
Scott Sharples2                           parameters were computed using a non-compartmental model. A linear mixed-effect
                                          model was used to analyze the logarithmically transformed AUC0-∞, AUC0-t and Cmax
    MDS Pharma Services                   as well as AUC0-30min and AUC0-60min. Tmax was analyzed by a signed rank test on the
                                          within-subject differences. The new formulation was well tolerated by the subjects.
                                          For both paracetamol and caffeine, the 90% confidence intervals for the ratios of
                                          AUC0-∞, AUC0-t, and Cmax for Extra Advance and current Extra, in both fasted and
                                          semi-fed states, all lied within the bioequivalence boundaries of [0.80, 1.25], except for
                                          paracetamol Cmax in the fasted state, which was [1.11, 1.30] (mean ratio was 1.20). The
                                          new formulation showed significantly greater early absorption (AUC0-30min and AUC0-
                                                ) for both paracetamol and caffeine compared to Panadol Extra (P<0.0001) in
                                          both fasted and semi-fed states (ratios in the range of 1.4 to 7.7). The new formulation
                                          showed significantly shorter Tmax for both paracetamol and caffeine (P<0.05), and
                                          paracetamol T4 (time to reach minimum therapeutic concentration in plasma of 4μg/
                                          ml) was twice as fast as Panadol Extra in both fasted and fed states. The new Panadol
                                          Extra Advnace formulation is bioequivalent to the currently marketed Panadol Extra
                                          formulation. Both paracetamol and caffeine are absorbed significantly faster with the
                                          new formulation compared to Panadol Extra.

                                               Dr. Dongzhou (Jeffery) Liu is working at GlaxoSmithKline as Medical Lead/Principal Clinical
                                            Investigator. Previously, he worked at Wyeth (now Pfizer) and Forest Labs with increasing
                                            responsibilities. His past 13 years’ industry experiences include pharmaceutical, preclinical, and
                                            clinical development of medical products with making key contribution in launching 7 marketed
                                            Rx drug products. The areas of his expertise include ADME/PK/BE/BA study, PK/PD modeling &
                                            simulation, IVIVC/IVIVE/IVMS, innovative drug design and delivery, Biopharmaceutical profiling.
                                            He obtained a PhD in Biochemistry, a MS in computer sciences, and a BS in Chemistry. He also
                                            obtained a EMBA. He has more than 50 publications and presented 20+ keynote speeches at
                                            global conferences. He is the lecture professor at SUNY-Old Westbury and Tianjin University
                                            School of Pharmacy. He is the members of NYAS, AAPS, ISSX, ACS, SAPA, etc.
                                                                                                          doi: 10.4172/0975-0851.1000105
Joint Meeting
                                         2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                         International Conference on Pharmaceutics & Novel Drug Delivery Systems

Bioavailability study of
Zolmitriptan sublingual                           S   ublingual tablet administration has an important field in therapy because of
                                                      taking immediate pharmacologic response, bypass of first pass effect and so high
                                                  bioavailability and patient satisfaction. Zolmitriptan is a good candidate as an active
tablets on Sheep model                            pharmaceutical ingredient in sublingual tablet formulations because of its freely
Ziya BAYRAK1, Cetin TAS1, Umut                    soluble in water, exposing first pass effect and high potency impact. Sublingual tablet
TASDEMIR2, Halil EROL2, Cansel KOSE               formulations were prepared with different polymers such as hydroxypropyl methyl
OZKAN1, Ayhan SAVASER1 and Yalcin                 cellulose (HPMC), chitosan and sodium carboxy methyl cellulose (CMCNa) with direct
OZKAN1                                            compression method. The effect of polymers has been investigated on in vitro and in
 Gulhane Military Medical Academy, Department     vivo drug studies. In vitro studies show that all formulations met the pharmacopeial
of Pharmaceutical Technology, Etlik 06018,        criteria. The optimum formulations for different ratios of polymers were chosen
Ankara, Turkey
                                                  for in vivo bioavailability studies on sheep model. A simple solution formulation
 Lalahan Livestock Central Research Institute,    of zolmitriptan was used for in vivo studies to calculate relative bioavailability of
06852 Lalahan, Ankara, Turkey
                                                  sublingual tablets. The results of in vivo studies showed that formulation containing
                                                  5% chitosan, has the maximum Cmax and AUC and minimum tmax values (p < 0.05).
                                                  Increasing the contact time with the sublingual mucosa with a mucoadhesive polymer
                                                  improve sublingual bioavailability and result in more predictable plasma levels of the
                                                  drug, leading to better therapeutic efficacy. As a result sublingual tablet administration
                                                  of zolmitriptan formulated with appropriate excipients and especially with chitosan
                                                  seems promising alternative to traditional routes.

                                                       Ziya Bayrak has begun doctoral studies in 2009. He continues doctorate education in
                                                    Gulhane Military Medical Academy, Department of Pharmaceutical Technology. The main fields
                                                    of research area are tablets, drug absorption and penetration from mucosa and skin.
                                                                                                          doi: 10.4172/0975-0851.1000105
Joint Meeting
                                     2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                     International Conference on Pharmaceutics & Novel Drug Delivery Systems

Enhanced oral
bioavailability of poorly                     B    icalutamide is a novel, orally active, non-steroidal anti-androgens used for the
                                                   treatment of prostate cancer. But its limited aqueous solubility leads to high
                                              variability in absorption after oral administration. To enhance the solubility and
water soluble drug via                        bioavailability of bicalutamide a novel nanocarriers system i.e. self-microemulsifying
Self-Microemulsifying                         drug delivery system (SMEDDS) has been successfully developed. Solubility of
Drug Delivery System                          bicalutamide was determined in various oils, surfactant and co-surfactant. On the
                                              basis of solubility studies, various SMEDDS formulations were prepared and ternary
(SMEDDS)                                      phase diagrams were plotted to identify the efficient self-emulsification region.
Akash Chaurasiya                              Once the microemulsion region was identified, SMEDDS at desired component
Matrix Laboratories Limited, India            ratios was prepared with bicalutamide (50 mgml-1). The formulation was then
                                              subjected to further characterization by dilution studies, droplet size, zeta potential
                                              and transmission electron miscroscopy (TEM). To investigate the release pattern
                                              of bicalutamide from SMEDDS, an in-vitro drug release study was done using USP
                                              dissolution apparatus in different dissolution media and compared with the release of
                                              bicalutamide from a conventional tablet. Oral pharmacokinetic study was performed
                                              in female Wistar rats (n=8) at the dose of 25 mg kg−1. The absorption of bicalutamide
                                              from SMEDDS form resulted in about 2.2-fold increase in bioavailability compared
                                              with the conventional tablet dosage form. Our studies illustrated the potential use of
                                              SMEDDS for the enhancement of bioavailability of hydrophobic compounds, such as
                                              bicalutamide and encourage further development of bicalutamide loaded SMEDDS as
                                              an oral drug delivery system.

                                                     Akash Chaurasiya had completed B. Pharm and M.Pharm (Pharmaceutics) from Department
                                               of Pharmaceutical Sciences, Dr H. S. Gour University Sagar (M.P.), India in the years 2004 and
                                               2007 respectively. He has also qualified GATE-2004 with percentile score of 92.72, conducted by
                                               IIT Delhi and received UGC Junior Research Fellowship for pursuing his M. Pharm degree. After
                                               the completion of post graduate studies he worked as a research scientist for 1 year in Dabur
                                               Research Foundation, Ghaziabad a renowned pharmaceutical company in India. In May 2008,
                                               Mr. Chaurasiya has joined PhD programme in pharmaceutical sciences under the guidance of
                                               Prof. R. K. Khar in Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University,
                                               New Delhi. During the PhD research work he was selected for Federal Commission Scholarship
                                               programme provided by Swiss Government, under which he was able to pursue a part of his PhD
                                               work from School of Pharmaceutics and Biopharmaceutics, University of Geneva, Switzerland
                                               for the time period of 9 months, from Sept.’09 to June’10. Presently, he has joined back Hamdard
                                               University, India and working as a senior research fellow for the completion PhD thesis work.
                                               Mr. Chaurasiya has an experience of approximately 5 years in pharmaceutical research and his
                                               areas of scientific interest are:

                                                   •     Oral bioavailability enhancement of active moieties which belongs to BCS class II & IV

                                                   •     Site specific targeting of anticancer drugs using biomolecules for better efficacy and
                                                         low toxicity

                                                   •     Delivery of bio-therapeutics via ocular route

                                                    Mr. Chaurasiya has published four research articles in reputed international research
                                               journals and attended a number of national and international conferences. He has also co-
                                               authored a book entitled “Pharmaceutics-II” which was awarded as a best pharmacy book in
                                               hindi language by All India Council for Technical Education (AICTE), India.
                                                                                                        doi: 10.4172/0975-0851.1000105
Joint Meeting
                                         2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                         International Conference on Pharmaceutics & Novel Drug Delivery Systems

Compelling Reasons for                             
                                                    Emerging markets are no more an option, but a strategic imperative for global
                                                    clinical research
Doing Bio Equivalence
Studies in India                                   
                                                    India is one of the fastest growing clinical research destination with a growth rate
                                                    2-1/2 times the overall market growth.
Mak Jawadekar
Director Research , Pfizer Inc, Connecticut, USA
                                                    the world’s third largest producer of drugs by volume, with drug research and
                                                    development work force, india is a major player in the pharmaceutical industry.
                                                    India has over 100 fda approved manufacturing units. India has filed the maximum
                                                    number of andas in the us almost equivalent or more than the number of andas
                                                    filed by us companies.
                                                    Indias clinical research landscape is undergoing a glorious metamorphosis, aided
                                                    by uniquely differentiating capabilities, a rapidly transforming health care market
                                                    and an enabling environment i.e rapidly adopting itself to global standards.
                                                    India’s strength in formulation development, new drug delivery system and
                                                    backed by excellent chemistry and bio analytical technics has brought down cost
                                                    of bio equivalence studies dramatically and without compromising international
                                                    India is rated as one of the most attractive destinations for clinical trials and bio
                                                    equivalence studies by various surveys.
                                                    India’s capability in bio equivalence has evolved with exceptionally good knowledge,
                                                    highly trained and skilled technical man power in bio analytical services including
                                                    method development validation and sample processing with strict adherence to
                                                    cfr part xi.
                                                    Huge volunteer data base, experience & knowledgable ethics committee, new
                                                    schedule y of the regulators enables compliance with global regulations.
                                                    had an opportunity to audit one of the leading ba/be centres in india namely,
                                                    quest life sciences
                                                    is centre is audited and approved by usfda having 100 beds clinical facility and a
                                                    good bio analytical laboratory, has filed over 30 andas in the us.
                                                    ey have a volunteer data base over 3000 subjects and in addition over 800 post
                                                    menopausal women subjects.
                                                    e company has even conducted bio equivalence studies on cancer patients.
                                                    ese studies have been filed in the us besides european regulatory requirements.
                                                    ey have faced innumerable audits from international clients, mainly from the
                                                    us and europe.
                                                    was surprised to find that the cost of the ba/be studies in india is less than half
                                                    of the study conducted in the us besides study schedules is one of the fastest as
                                                    compared to many other centres outside india.
                                                    Quest has made a couple of para iv filings.
                                                    slide show of one of the facilities is available on request.
                                                                                                doi: 10.4172/0975-0851.1000105
Joint Meeting
                              2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                              International Conference on Pharmaceutics & Novel Drug Delivery Systems

of rofecoxib following                 T    he potential gastrointestinal (GI) disorders associated with oral administration
                                            of rofecoxib can be avoided by delivering the drug to the inflammation site
                                       for sustained therapeutic action. Hyroxypropyl methylcellulose (HPMC), Sodium
topical administration in              alginate and Carbopol 940 were used to develop topical gel of rofecoxib. Rofecoxib
rat                                    encapsulated niosomes were prepared by lipid film hydration technique. The niosomal
Malay K Das and Abdul B Ahmed
                                       vesicles obtained were incorporated into blank carbopol gel to form niosomal gel.
                                       The effects of different variables on rofecoxib permeation from gel formulation was
Dibrugarh University, India
                                       evaluated using cellulose membrane, rat epidermis and pig ear epidermis mounting
                                       on a Keshary-Chien glass diffusion cell. The anti-inflammatory activity of rofecoxib
                                       gel was evaluated using carrageenan-induced rat hind paw edema model. The
                                       niosomal gel showed a prolong drug release behavior as compared to plain drug gel.
                                       The differential scanning calorimetric study of drug loaded gel and pig epidermis after
                                       permeation study confirmed the inertness of the carbopol gel base towards rofecoxib
                                       and absence of drug metabolism in the skin during permeation study, respectively. The
                                       anti-inflammatory activity of 4% w/w sodium alginate-carbopol 940 gel containing 25
                                       % w/w rofecoxib in the rat hind paw edema model reveals that rofecoxib was delivered
                                       to the inflammation site at a controlled level over a period of 6 h. These results suggest
                                       the feasibility of topical administration of rofecoxib with avoidance of major GI
                                       disorders associated with peroral rofecoxib.

                                            Dr. Malay K Das has completed his Ph. D. degree from Jadavpur University, Kolkata,
                                         India. He is currently serving as Assistant Professor (Pharmaceutics) in the Department of
                                         Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India. He has supervised 16 M.
                                         Pharm. thesis and 5 Ph. D. theses yet to be submitted under his guidance. He has published
                                         more than 20 research papers in various national and international journals.
                                                                                                          doi: 10.4172/0975-0851.1000105
Joint Meeting
                                        2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                        International Conference on Pharmaceutics & Novel Drug Delivery Systems

Synthesis and
anticancer evaluation of                         C     ertain 4-anilinofuro[2,3-b]quinoline derivatives were synthesized and evaluated
                                                       for their anticancer activities against human cervical epithelioid carcinoma
                                                 (HeLa), hepatocelluar carcinoma (SKHep1), oral squamous cell carcinoma (SAS),
Furoquinoline derivatives                        human stomach adenocarcinoma (AGS), non-small cell lung cancer (A549), and
Cherng-Chyi Tzeng, Yu-Wen Chen, and              esophageal carcinoma (CE81T). Among these compounds tested, 1-[4-(furo[2,3-b]
Yeh-Long Chen                                    quinolin-4-ylamino)phenyl]ethanone (1) was the most potent with mean GI50
College of Life Science, Kaohsiung Medical       values of less than 4.2 micromole respectively against the growth of HeLa, SKHep, and
University, Taiwan                               CE81T cells and therefore, was further evaluated on its effects of cell cycle distribution.
                                                 Results indicated that lead compound 1 induces cell cycle arrest in G2/M followed by
                                                 apoptosis. However, some drawbacks such as lack of selective cytotoxicity, poor oral
                                                 bioavailability, and poor water solubility exhibited by 1 prompted us to search for
                                                 newer derivatives with better pharmacokinetic profiles and higher water solubility.
                                                 Various aminoalkoxyimino derivatives of 1 have been synthesized and evaluated.
                                                 Some of them exhibited selective anticancer activity against the growth of non-small
                                                 cell lung cancers (especially NCI-H460) and higher water solubility than the lead
                                                 compound. Xenograghic studies and orthotropic lung cancer model in nude mice
                                                 using H1229 cells indicated that certain aminoalkoxyimino derivatives of 1 exhibited
                                                 significant efficacy in inhibiting tumor growth in vivo. Further structural optimization
                                                 and mechanism studies are on-going.

                                                     Dr. Cherng-Chyi Tzeng has completed his Ph. D degree from the University of Rhode Island,
                                                   USA in 1984. He is the Dean of General Affairs at Kaohsiung Medical University, Taiwan. He
                                                   has published more than 120 papers in reputed journals and serving as an editorial board
                                                   member of Kaohsiung Journal of Medical Sciences (SCI Journal).
                                                                                                          doi: 10.4172/0975-0851.1000105
Joint Meeting
                                    2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                    International Conference on Pharmaceutics & Novel Drug Delivery Systems

Inhibition of vascular
smooth muscle cell                           A     bnormal proliferation of vascular smooth muscle cells (VSMCs) play important
                                                   roles in the development of cardiovascular diseases. PMC (2,2,5,7,8-pentamethyl-
                                             6-hydroxychromane) is the most potent hydrophilic derivative of the vitamin E. In
proliferation of Vitamin                     this study, we investigated the inhibitory mechanisms of PMC on VSMC proliferation
E derivative Pentamethyl                     in vitro and in vivo. PMC (20 and 50 μM) obviously suppressed cell proliferation of
hydroxychromane                              PDGF-BB-stimulated cells but not resting cells, and arrested cell cycle progression at
                                             the G2/M phase. A significant reduction of neointimal formation in carotid arteries
Joen-Rong Sheu                               was observed in PMC (5 mg/kg/day)-treated rats after balloon angioplasty. Activations
Taipei Medical University, Taiwan            of STAT3, JAK2, PLCγ1, PKCδ, and ROS, but not ERK1/2, AKT, or PKCα, were
                                             markedly inhibited by PMC in PDGF-BB-stimulated VSMCs. Deferoxamine and
                                             PMC significantly inhibited the phosphorylation of PLCγ1 and JAK2 and arrested
                                             cell cycle progression at the G2/M phase. These events, however, were reversed in the
                                             presence of Fe2+. Moreover, PMC directly inhibited hydroxyl radical formation in
                                             both the Fenton reaction and VSMCs according to an electron spin resonance study.
                                             In conclusion, this study demonstrates for the first time that PMC inhibited VSMC
                                             proliferation in vitro, and balloon injury-induced neointimal formation in vivo. The
                                             inhibitory mechanisms of PMC may be involved in the inhibition of hydroxyl radical-
                                             mediated PLCγ1-PKCδ and JAK2-STAT3 activation, and causes cell cycle arrest at the
                                             G2/M phase. PMC treatment may represent a novel approach for lowering the risk of
                                             or improving the function in abnormal VSMC proliferation-related vascular diseases.

                                                 Dr. Joen-Rong Sheu., Graduate Institute of Medical Sciences, Taipei Medical University; Educa-
                                              tion: 1988-1992 Ph.D., Institute of Pharmacology, College of Medicine, National Taiwan University.
                                              Current position and professional experience: Deputy Dean, College of Medicine; Director,
                                              Department of Pharmacology, Taipei Medical University.

                                                Fields of specialty: Molecular Pharmacology, Tumor Biology, Protein Chemistry, Signal
                                              Transduction. Major awards and honors: Wang Ming-Ning Memorial Research Awards (1991),
                                              Taipei, Taiwan; Research Award of National Science Council (1995-2001), Taipei, Taiwan;
                                              Academic Award of American Huang Chi-Hsing Fundation, American (1997; 2001); Research
                                              Award of Lee Hung-Hsin Fundation, Taipei, Taiwan; Outstanding Research Award, Taipei
                                              Medical University, Taipei, Taiwan (1999-2010).
                                                                                                                doi: 10.4172/0975-0851.1000105
Joint Meeting
                                          2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                          International Conference on Pharmaceutics & Novel Drug Delivery Systems

The FAF-Drugs server:
A multi-step engine                                   V    irtual ligand screening can help to prioritize compounds for experimental
                                                           screening and identification of hit compounds modulating the function(s) of
                                                      a macromolecular target (e.g., a protein involved in the pathogenesis of a disease).
to prepare electronic                                 As such, the concept of screening of high quality compound collections in terms
chemical compound                                     of improved ADMET (absorption, distribution, metabolism, excretion, toxicity)
collections                                           properties and containing a reduced number of “nuisance compounds” is gaining
                                                      momentum. Clearly, library design with soft and appropriate ADMET filtering,
David Lagorce1, Julien Maupetit1,                     removal of undesirable molecules/groups and with parameters tailored to a given
Jonathan Baell2, Olivier Sperandio1,
                                                      project and/or to the stage of the project is nowadays considered critical to both,
Pierre Tufféry1, Maria A. Miteva1,
Hervé Galons3 and Bruno O.
                                                      drug discovery and chemical biology endeavors. These observations motivated us to
Villoutreix1                                          develop an online tool, the FAF-Drugs2 server, dedicated to the preparate compound
                                                      collections prior to virtual ligand screening and assists hit selection / lead optimization
  MTi laboratory - Paris Diderot University, France
  The Walter and Eliza Hall Institute of Medical      before chemical synthesis or ordering. To our knowledge, such a free service able to
Research, Australia                                   handle several thousands of compounds with either predefined filtering parameters
  Paris Descartes University, France                  or user-tuned parameters, and assisting decision-making is not available at present.
                                                      The FAF-Drugs2 server is based on a significantly improved version of a previously
                                                      published standalone pack and has been designed through a user-centered approach
                                                      with emphasis on user-friendliness. Our online toolkit allowing to prepare large
                                                      compound libraries and now includes among others, the detection of PAINS (Pan
                                                      Assay Interference Compounds) and various oral bioavailability evaluations. The
                                                      FAF-Drugs2 server will soon available in the next few weeks.

                                                           David Lagorce is working as an INSERM Engineer and he is a Ph.D student at the MTi
                                                        laboratory – Paris Diderot University - PARIS - FRANCE. He is working on new tools for ADMET
                                                        prediction and chemical libraries preparation.
                                                                                                             doi: 10.4172/0975-0851.1000105
Joint Meeting
                                         2nd World Congress on Bioavailability & Bioequivalence: Pharmaceutical R & D Summit-2011

                                         International Conference on Pharmaceutics & Novel Drug Delivery Systems

Pharmacokinetics profile
of Tulathromycin in                                 T    ulathromycin is a novel long-acting semi-synthetic macrolide antibiotic of the
                                                         triamilide group that is used in the treatment of respiratory diseases in cattle
                                                    and pigs. The pharmacokinetics of tulathromycin were determined in five lactating
Egyptian lactating goats                            goats following single intravenous and intramuscular injections of 2.5 mg/kg BW
Aziza M.M.Amer                                      with a 6 week interval between injections. Plasma, milk and urine concentrations of
Faculty of Veterinary Medicine, Cairo University,
                                                    tulathromycin were determined using a microbiological assay method.
                                                        Following a single intravenous injection of tulathromycin formulation, the
                                                    concentration-time curves were best described by a two compartment open model.
                                                    Tulathromycin had a high volume of distribution (VSS, 16.1 ± 2.0 L/kg) and was
                                                    slowly cleared from the central compartment (126 ± 4 Tulathromycin was
                                                    detected in the milk of goats 30 minutes after IV injection with mean concentration
                                                    of 0.15 ± 0.03 μ and persisted for 21 days over target MIC. Tulathromycin was
                                                    detected in the urine from 0.5 to 96 hours after IV injection and exceeded the target
                                                    MIC for 14 days hours post injection. Plasma protein binding was 22.8%.
                                                        Following a single intramuscular injection of tulathromycin formulation, the
                                                    maximum plasma concentration (0.73 ± 0.07 μ was reached at 0.5 hour and
                                                    detectable tulathromycin concentrations were present in the plasma for up to 168
                                                    hours. Tulathromycin was rapidly absorbed (t½ab, 0.104 ± 0.02 hour) and slowly
                                                    eliminated (t0.5β, 99.4 ± 11.2 h.) after IM injection. The calculated MRTinfinity was 166.3
                                                    ± 21.9 h and bioavailability was 95.8 ± 6.5%. Tulathromycin rapidly penetrated into
                                                    milk with high Cmax-milk to Cmax-plasma ratio and AUCmilk to AUCplasma ratio. Tulathromycin
                                                    persisted in urine samples for 13 days post-injection.

                                                          Aziza Mahrous Amer has completed her Ph. D at the age of 26 years from Cairo University
                                                     and postdoctoral studies from Cairo University. She is Professor of Pharmacology, Faculty
                                                     of Veterinary Medicine Cairo University. She has published more than 50 papers in reputed
                                                     journals and serving as an editorial board member of repute. The areas of reseaches are
                                                     Pharmacokinetics – Pharmacodynamics Pharmacokinetic interactions, Evaluation of new drug
                                                     of plants and natural origin.

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